Project Abstract/Summary The last decade has seen rapid progress in identifying genetic variants that confer disease risk. However, the biological context in which these variants exert their influence is not fully understood. For example, cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop COPD, suggesting that genetics may play a role in the pathogenesis of COPD. Genome- wide association studies have identified more than twenty genetic loci associated with COPD status. However, these single nucleotide polymorphisms (SNPs) only explain a small amount of the phenotypic variance of COPD. This suggests that many variants of weak phenotypic effect work together to influence COPD pathobiology. One of the challenges now for pulmonary geneticists is to understand how these many SNPs work together to influence biological function, and to identify the contexts in which those functions are important. Given that disease-associated SNPs often do not alter protein coding, these SNPs likely influence cellular phenotypes through regulatory control of gene expression. We propose to develop new regulatory network models for modeling the collective effect of disease- associated SNPs across tissues and on exposures such as cigarette smoke. We will then apply these methods to better understand the context-specific regulatory function of variants associated with COPD. Dr. Platig?s training in physics, complex systems, and genomics has well prepared him to carry out this research. However, additional training in statistical genetics, functional genomics, network theory, and pulmonary biology will aid in his scientific and professional development as he starts his faculty position at the Channing Division of Network Medicine (CDNM) in the summer of 2018. With a blend of formal coursework, intensive workshops, and interdisciplinary mentoring, Dr. Platig will obtain the necessary skills to achieve his goals. The CDNM and Harvard Medical School provide outstanding opportunities for research and training in the systems genetics of pulmonary disease, with four teaching hospitals and two Harvard schools within a five block radius. Dr. Platig will have access to extensive computing resources through his primary mentor, Dr. Silverman, and through his co-mentor Dr. Quackenbush. In addition, Dr. Platig will attend regular meetings with pulmonologists, statistical geneticists, and physicians to get regular feedback on his research and training. This combination of research and training will prepare Dr. Platig for identifying and tackling the open challenges in the systems genetics of pulmonary disease.